The Immunology of COVID-19 Flashcards
1
Q
SARS-CoV-2 and related viruses: SARS and common cold
A
2
Q
SARS-CoV-2 is a …-sense, …-stranded RNA virus
A
SARS-CoV-2 is a positive-sense, single-stranded RNA virus
3
Q
SARS-CoV-2 and related viruses: basics
- SARS-CoV-2 is a …-sense, single-stranded … virus
- Infects … and …
- Replication and gene expression occurs in the … of the host cell
- Can use … cell proteins during replication and gene expression
- Express … proteins separately from non-… ones
- … proteins are expressed from a set of subgenomic mRNAs (require replication for expression)
A
- SARS-CoV-2 is a positive-sense, single-stranded RNA virus
- Infects vertebrates and invertebrates
- Replication and gene expression occurs in the cytoplasm of the host cell
- Can use host cell proteins during replication and gene expression
- Express structural proteins separately from non-structural ones
- Structural proteins are expressed from a set of subgenomic mRNAs (require replication for expression)
4
Q
SARS-CoV-2 and related viruses: basics
- SARS-CoV-2 is a positive-sense, single-stranded RNA virus
- Infects vertebrates and invertebrates
- … and … expression occurs in the cytoplasm of the host cell
- Can use host cell proteins during … and … expression
- Express structural proteins … from non-structural ones
- Structural proteins are expressed from a set of … mRNAs (require replication for expression)
A
- SARS-CoV-2 is a positive-sense, single-stranded RNA virus
- Infects vertebrates and invertebrates
- Replication and gene expression occurs in the cytoplasm of the host cell
- Can use host cell proteins during replication and gene expression
- Express structural proteins separately from non-structural ones
- Structural proteins are expressed from a set of subgenomic mRNAs (require replication for expression)
5
Q
SARS-CoV-2 and related viruses: cell entry
A
6
Q
SARS-CoV-2 and related viruses: cell/tissue tropism
- Tissue tropism is largely determined by … expression
- In most tissues, what cells are infected? (2)
A
- Tissue tropism is largely determined by ACE2 expression
-
In most cells - EC and VEC INFECTED
- Lungs: basal ciliated and club cells, proliferative EC1, AT2 cells2, VEC3
- Trachea: ciliated and goblet cells of mucosa, EC of conduits and glands
- Intestines: EC in mucosa and glands
- Skin: secretory luminal cells in sweat glands, VEC
- Kidneys: EC in the distal tubule and collecting ducts, VEC
- Pancreas: EC in Langerhans glands and intra-islet ducts, VEC
- Brain: VEC
- Heart: VEC
- 1EC=epithelial cell, 2AT2 =alveolar type 2 cell, 3VEC=vascular endothelial cell
7
Q
SARS-CoV-2 and related viruses: target tissues and symptoms
- Important target tissues
- Lung – … (pneumonia)
- Vasculature – … (contributing to thrombotic events)
- Gut – epithelial cells, lymphocytes (…, pain, loos of …)
- CNS – vasculitis (C…)
- Muscle – fatigue/weakness, M…
- Naso and oropharynx (sensory neuroepithelium) – loss of … and …
A
- Important target tissues
- Lung – pneumocytes (pneumonia)
- Vasculature – vasculitis (contributing to thrombotic events)
- Gut – epithelial cells, lymphocytes (diarrhea, pain, loos of appetite)
- CNS – vasculitis (confusion)
- Muscle – fatigue/weakness, myalgia
- Naso and oropharynx (sensory neuroepithelium) – loss of smell and taste
8
Q
SARS-CoV-2 and related viruses: target tissues and symptoms
- Important target tissues
- … – pneumocytes (pneumonia)
- … – vasculitis (contributing to thrombotic events)
- … – epithelial cells, lymphocytes (diarrhea, pain, loos of appetite)
- … – vasculitis (confusion)
- … – fatigue/weakness, myalgia
- … and … (sensory neuroepithelium) – loss of smell and taste
A
- Important target tissues
- Lung – pneumocytes (pneumonia)
- Vasculature – vasculitis (contributing to thrombotic events)
- Gut – epithelial cells, lymphocytes (diarrhea, pain, loos of appetite)
- CNS – vasculitis (confusion)
- Muscle – fatigue/weakness, myalgia
- Naso and oropharynx (sensory neuroepithelium) – loss of smell and taste
9
Q
SARS-CoV-2 and related viruses: infection in animals
- Coronaviruses may infect a wide variety of animals, both terrestrial and aquatic, domestic and wild.
A
- Coronaviruses may infect a wide variety of animals, both terrestrial and aquatic, domestic and wild.
10
Q
SARS-CoV-2 and related viruses: animals
- Horseshoe bats harbour the bat coronavirus RaTG13 which exhibits 97.4% amino acid identity with SARS-CoV-2 in the Spike protein
- But bats don’t seem to get sick from coronaviruses
- Bats have … body temperature of about 39 C (related to heir ability to fly), this might work a bit like a …
- They also have a … in STING (Stimulator of Interferon Genes). This is the main adaptor in several DNA-sensing pathways. The … makes it less potent, so that less … is being produced.
- This reduces …
A
- Horseshoe bats harbour the bat coronavirus RaTG13 which exhibits 97.4% amino acid identity with SARS-CoV-2 in the Spike protein
- But bats don’t seem to get sick from coronaviruses
- Bats have higher body temperature of about 39 C (related to heir ability to fly), this might work a bit like a fever.
- They also have a mutation in STING (Stimulator of Interferon Genes). This is the main adaptor in several DNA-sensing pathways. The mutation makes it less potent, so that less interferon is being produced.
- This reduces inflammation
11
Q
SARS-CoV-2 and related viruses: animals
- Horseshoe bats harbour the bat coronavirus RaTG13 which exhibits 97.4% amino acid identity with SARS-CoV-2 in the Spike protein
- But bats don’t seem to get … from coronaviruses
- Bats have higher body temperature of about … C (related to heir ability to fly), this might work a bit like a fever.
- They also have a mutation in S…. This is the main adaptor in several DNA-sensing pathways. The mutation makes it less potent, so that less interferon is being produced.
- This reduces inflammation
A
- Horseshoe bats harbour the bat coronavirus RaTG13 which exhibits 97.4% amino acid identity with SARS-CoV-2 in the Spike protein
- But bats don’t seem to get sick from coronaviruses
- Bats have higher body temperature of about 39 C (related to heir ability to fly), this might work a bit like a fever.
- They also have a mutation in STING (Stimulator of Interferon Genes). This is the main adaptor in several DNA-sensing pathways. The mutation makes it less potent, so that less interferon is being produced.
- This reduces inflammation
12
Q
Genome structure & protein expression
- The genome translates into about … expressed proteins. Major proteins are
- The … protein or (S-protein)
- The … (E) protein
- The … protein (M-protein) and
- The … protein (N-protein)
- The size of the genome is about 30kb (HIV 9.2 kb, CMV 230 kb)
- Total protein length in amino acids is about …
A
- The genome translates into about 30 expressed proteins. Major proteins are
- The spike protein or (S-protein)
- The envelope (E) protein
- The membrane protein (M-protein) and
- The nucleocapsid protein (N-protein)
- The size of the genome is about 30kb (HIV 9.2 kb, CMV 230 kb)
- Total protein length in amino acids is about 9000
13
Q
Genome structure & protein expression
- List of SARS-CoV-2 proteins/size
- Size corresponds to the relative number of potential …-cell and …-cell …
A
- List of SARS-CoV-2 proteins/size
- Size corresponds to the relative number of potential B-cell and T-cell epitopes
14
Q
Genome structure & protein expression
- The spike protein has 2 subunits, … and …
- The … subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2
- … subunit mediates viral cell membrane fusion
A
- The spike protein has 2 subunits, S1 and S2
- The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2
- TheS2 subunit mediates viral cell membrane fusion
15
Q
General interaction with the immune system: overview (COVID-19)
A
16
Q
… immunity is our first line defence against pathogens and its proper functioning may be a crucial contributor to … courses of COVID-19.
A
Innate immunity is our first line defence against pathogens and its proper functioning may be a crucial contributor to asymptomatic courses of COVID-19.
17
Q
Innate immunity is our first line defence against pathogens and its proper functioning may be a crucial contributor to asymptomatic courses of COVID-19
- Is there a way of improving innate immunity?
A
There is no classic memory by way or training cells with specific receptors but ‘trained immunity’ has been described:
18
Q
Innate Immunity: How can it be trained?
A
19
Q
Trained immunity is the result of ‘firing up’ immunity by stimuli/events that stimulate the same … immune cells that are required to protect us from …
A
Trained immunity is the result of ‘firing up’ immunity by stimuli/events that stimulate the same innate immune cells that are required to protect us from infection
- This could be recent vaccination even if completely unrelated to the infectious agent that is dealt with more effectively as a result
- It could also be the result of a recent infection
- It may be achievable by vaccine adjuvants alone or by other substances like plant lectins.
- The fact that in older people innate immunity is often reduced may be one reason why older people are more likely to have severe COVID-19
- Some researchers suggested using the TB vaccine to protect against COVID-19. This is not completely implausible, but we now have better ways of vaccinating)
20
Q
Trained Immunity
- Trained immunity is the result of ‘firing up’ immunity by stimuli/events that stimulate the same innate immune cells that are required to protect us from infection
- This could be recent … even if completely unrelated to the infectious agent that is dealt with more effectively as a result
- It could also be the result of a recent …
- It may be achievable by vaccine … alone or by other substances like plant …
- The fact that in older people innate immunity is often … may be one reason why … people are more likely to have … COVID-19
- Some researchers suggested using the … vaccine to protect against COVID-19. This is not completely implausible, but we now have better ways of vaccinating)
A
- Trained immunity is the result of ‘firing up’ immunity by stimuli/events that stimulate the same innate immune cells that are required to protect us from infection
- This could be recent vaccination even if completely unrelated to the infectious agent that is dealt with more effectively as a result
- It could also be the result of a recent infection
- It may be achievable by vaccine adjuvants alone or by other substances like plant lectins.
- The fact that in older people innate immunity is often reduced may be one reason why older people are more likely to have severe COVID-19
- Some researchers suggested using the TB vaccine to protect against COVID-19. This is not completely implausible, but we now have better ways of vaccinating)
21
Q
B-cells and antibodies: blocking entry
A
22
Q
B-cells and antibodies: timeline
“Serologic responses to SARS-CoV-2 infection among hospital staff with mild disease in eastern France”
- 90% … Ab 2-3 weeks after onset of symptom, almost all 4 weeks after
- … made later
A
- 90% IgM Ab 2-3 weeks after onset of symptom, almost all 4 weeks after
- IgG made later
23
Q
B-cells and antibodies: IgM / IgG
- Consistent antibody responses are detectable to the spike protein S… subunit and … protein throughout
A
- Consistent antibody responses are detectable to the spike protein S2 subunit and N protein throughout
24
Q
B-cells and antibodies: protective efficacy
- A study in health care workers in 2020 provided an estimate of protection by antibodies over 7 months. 12541 individuals were tested at baseline.
- Of 11364 individuals (90.6%) who were seronegative for anti-spike antibody at baseline
- 88 converted to seropositive during the study
- Their risk was estimated to be 0.60 per 10,000 days at risk
- Of 1177 (9.4%) who were seropositive for anti-spike antibody at baseline.
- 2 were reinfected during the study (new positive PCR)
- Their overall risk was estimated at 0.13 per 10,000 days at risk
- Following adjustment for covariates, an incidence rate ratio (IRR) of 0.11 was calculated. This translated into an efficacy of ..%.
A
- A study in health care workers in 2020 provided an estimate of protection by antibodies over 7 months. 12541 individuals were tested at baseline.
- Of 11364 individuals (90.6%) who were seronegative for anti-spike antibody at baseline
- 88 converted to seropositive during the study
- Their risk was estimated to be 0.60 per 10,000 days at risk
- Of 1177 (9.4%) who were seropositive for anti-spike antibody at baseline.
- 2 were reinfected during the study (new positive PCR)
- Their overall risk was estimated at 0.13 per 10,000 days at risk
- Following adjustment for covariates, an incidence rate ratio (IRR) of 0.11 was calculated. This translated into an efficacy of 89%.
25
Q
For vaccines, vaccine efficacy (VE) can be calculated in the same way:
A
VE = 1 – (IRvaccinated/IRnon-vaccinated)=1-IRR
26
Q
B-cells and antibodies: neutralising titres
- Determining neutralising antibody titres requires an … system that allows precise detection of infection relative to … levels.
A
- Determining neutralising antibody titres requires an experimental system that allows precise detection of infection relative to antibody levels.
27
Q
B-cells and antibodies: timeline of decay
- Immunological memory to SARS-CoV-2 assessed for up to … months after infection
- Longitudinal data on neutralising antibody titres (serum dilutions) shows a … of neutralising capacity and allows an estimate of the duration of protection if the levels required for protection are know.
A
- Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection
- Longitudinal data on neutralising antibody titres (serum dilutions) shows a decline of neutralising capacity and allows an estimate of the duration of protection if the levels required for protection are know.
28
Q
B-cells and antibodies: time-line of decay
- “Neutralizing antibody levels are … predictive of immune protection from … SARS-CoV-2 infection”
A
“Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection”
29
Q
B-cells and antibodies: the concern with variants
- Mutations occur in all SARS-C0V-2 proteins, however, those in the … protein are most concerning because the development of therapeutics has -focused on the … protein. This is because the … protein is crucial for viral entry into cells.
A
- Mutations occur in all SARS-C0V-2 proteins, however, those in the Spike protein are most concerning because the development of therapeutics has -focused on the Spike protein. This is because the Spike protein is crucial for viral entry into cells.
33
Q
B-cells and antibodies: SARS-CoV-2 variants
A
43
Q
T-cells: the search for the best target proteis/epitopes
- Some peptides recognised by T-cells in SARS-CoV-1 infection, the infection causing the 2002/2003 SARS epidemic, were identified in the past
- Some of them occur … in SARS-CoV-2
- There also is some homology between the … … coronaviruses (OC43, E229, NL63, HKU1) and SARS-CoV-2
A
- Some peptides recognised by T-cells in SARS-CoV-1 infection, the infection causing the 2002/2003 SARS epidemic, were identified in the past
- Some of them occur identically in SARS-CoV-2
- There also is some homology between the common cold coronaviruses (OC43, E229, NL63, HKU1) and SARS-CoV-2
44
Q
T-cells: recognition of SARS-CoV-2 peptide pools
- CD4 T-cells recognise essentially … SARS-CoV-2 proteins.
- … differences between unexposed and exposed individuals were found for spike, NCAP, VME, VEMP, ORF3b, and NSP3a
A
- CD4 T-cells recognise essentially all SARS-CoV-2 proteins.
- Significant differences between unexposed and exposed individuals were found for spike, NCAP, VME, VEMP, ORF3b, and NSP3a
45
Q
T-cells: CD8 T-cell responses peak around day 30
and … over time (COV-19)
A
T-cells: CD8 T-cell responses peak around day 30
and decline over time (COV-19)
46
Q
T-cells: CD8 T-cell responses peak around day 30
and … over time (COV-19)
A
T-cells: CD8 T-cell responses peak around day 30
and decline over time (COV-19)
49
Q
T-cells: HLA-disease associations with respect to CoVID-19
- There is … evidence for associations of HLA-type and COVID-19 severity at this time
- Due to the huge … of the HLA locus, very large studies will be required in future to prove or disprove significant HLA-associations
- If found, such associations may inform vaccine strategies
A
- There is limited evidence for associations of HLA-type and COVID-19 severity at this time
- Due to the huge polymorphisms of the HLA locus, very large studies will be required in future to prove or disprove significant HLA-associations
- If found, such associations may inform vaccine strategies
50
Q
T-cells: HLA-disease associations with respect to CoVID-19
- There is limited evidence for associations of HLA-type and COVID-19 severity at this time
- Due to the huge polymorphisms of the HLA locus, very large studies will be required in future to prove or disprove significant HLA-associations
- If found, such associations may inform … strategies
A
- There is limited evidence for associations of HLA-type and COVID-19 severity at this time
- Due to the huge polymorphisms of the HLA locus, very large studies will be required in future to prove or disprove significant HLA-associations
- If found, such associations may inform vaccine strategies
51
Q
T-cells: HLA-disease associations with respect to CoVID-19
- HLA/Disease associations can be based on T-cell recognition of peptides presented by HLA-molecules
- May explain the role of biogeographical ancestry in disease …
- Recently published results suggest that the presence of HLA-A*0201 and HLA-A*0301 are associated with a … risk, but HLA-A*0101 with a … risk of death in older people (>60 years)
A
- HLA/Disease associations can be based on T-cell recognition of peptides presented by HLA-molecules
- May explain the role of biogeographical ancestry in disease susceptibility
- Recently published results suggest that the presence of HLA-A*0201 and HLA-A*0301 are associated with a lower risk, but HLA-A*0101 with a higher risk of death in older people (>60 years)
52
Q
Immunity in high-risk groups
- Some underlying diseases associated with fatal COVID-19 outcome may represent immunological risk factors, others simply weaken the patient
- 7 FACTORS - list
A
- Some underlying diseases associated with fatal COVID-19 outcome may represent immunological risk factors, others simply weaken the patient
53
Q
Immunity in high-risk groups
- Some underlying diseases associated with fatal COVID-19 outcome may represent immunological risk factors, others simply weaken the patient
- Fill in the blanks
A
- Some underlying diseases associated with fatal COVID-19 outcome may represent immunological risk factors, others simply weaken the patient
60
Q
Vaccines: RNA-based COVID-19 vaccines
- RNA vaccines use … RNA (mRNA) in order to achieve the production of relevant proteins of a … in host cells. Just as a reminder, RNA is composed of adenine (A), cytosine (C), guanine (G), and uracil (U). RNA vaccines are not integrated into the recipient’s …. In order to reach the inside of a cell, mRNA needs to be stabilised and packaged. Protein will be expressed in the injected tissues (i.e. muscle cells)
- Stability is achieved by
- A specially modified Nucleotide positioned at the 5’ end (Cap)
- A poly (A) tail
- Composition and structure of the 3’ untranslated regions (3’UTR) contribute to intracellular mRNA stability.
A
- RNA vaccines use messenger RNA (mRNA) in order to achieve the production of relevant proteins of a pathogen in host cells. Just as a reminder, RNA is composed of adenine (A), cytosine (C), guanine (G), and uracil (U). RNA vaccines are not integrated into the recipient’s genome. In order to reach the inside of a cell, mRNA needs to be stabilised and packaged. Protein will be expressed in the injected tissues (i.e. muscle cells)
- Stability is achieved by
- A specially modified Nucleotide positioned at the 5’ end (Cap)
- A poly (A) tail
- Composition and structure of the 3’ untranslated regions (3’UTR) contribute to intracellular mRNA stability.
61
Q
Vaccines: RNA-based COVID-19 vaccines
- RNA vaccines use messenger RNA (mRNA) in order to achieve the production of relevant proteins of a pathogen in host cells. Just as a reminder, RNA is composed of adenine (A), cytosine (C), guanine (G), and uracil (U). RNA vaccines are not integrated into the recipient’s genome. In order to reach the inside of a cell, mRNA needs to be stabilised and packaged. Protein will be expressed in the injected tissues (i.e. muscle cells)
- Stability is achieved by
- A specially modified … positioned at the …’ end (Cap)
- A poly (A) tail
- Composition and structure of the …’ untranslated regions (3’UTR) contribute to intracellular mRNA stability.
A
- RNA vaccines use messenger RNA (mRNA) in order to achieve the production of relevant proteins of a pathogen in host cells. Just as a reminder, RNA is composed of adenine (A), cytosine (C), guanine (G), and uracil (U). RNA vaccines are not integrated into the recipient’s genome. In order to reach the inside of a cell, mRNA needs to be stabilised and packaged. Protein will be expressed in the injected tissues (i.e. muscle cells)
- Stability is achieved by
- A specially modified Nucleotide positioned at the 5’ end (Cap)
- A poly (A) tail
- Composition and structure of the 3’ untranslated regions (3’UTR) contribute to intracellular mRNA stability.
62
Q
Vaccines: RNA-based COVID-19 vaccines
- RNA vaccines use messenger RNA (mRNA) in order to achieve the production of relevant proteins of a pathogen in host cells. Just as a reminder, RNA is composed of adenine (A), cytosine (C), guanine (G), and … RNA vaccines are not integrated into the recipient’s genome. In order to reach the inside of a cell, mRNA needs to be stabilised and packaged. Protein will be expressed in the injected tissues (i.e. muscle cells)
- Stability is achieved by
- A specially modified Nucleotide positioned at the 5’ end (Cap)
- A … (A) tail
- Composition and structure of the 3’ … regions (3’UTR) contribute to intracellular mRNA stability.
A
- RNA vaccines use messenger RNA (mRNA) in order to achieve the production of relevant proteins of a pathogen in host cells. Just as a reminder, RNA is composed of adenine (A), cytosine (C), guanine (G), and uracil (U). RNA vaccines are not integrated into the recipient’s genome. In order to reach the inside of a cell, mRNA needs to be stabilised and packaged. Protein will be expressed in the injected tissues (i.e. muscle cells)
- Stability is achieved by
- A specially modified Nucleotide positioned at the 5’ end (Cap)
- A poly (A) tail
- Composition and structure of the 3’ untranslated regions (3’UTR) contribute to intracellular mRNA stability.
63
Q
Vaccines: RNA-based COVID-19 vaccines
- Cell entry is achieved by packaging in …. These are fragile and may be damaged and destroyed by …
- In the beginning, the mRNA vaccines were treated with extreme care. Doses were drawn up immediately prior to … and a fair number of doses was discarded as a … e.g. after dropping syringes.
- In some countries the guidance for the Pfizer/Biontech vaccine, for example, has been adjusted a little bit, to the extent that vaccine doses can be drawn up centrally and transported by car to vaccine centres.
A
- Cell entry is achieved by packaging in liposomes. These are fragile and may be damaged and destroyed by shaking.
- In the beginning, the mRNA vaccines were treated with extreme care. Doses were drawn up immediately prior to administration and a fair number of doses was discarded as a precaution e.g. after dropping syringes.
- In some countries the guidance for the Pfizer/Biontech vaccine, for example, has been adjusted a little bit, to the extent that vaccine doses can be drawn up centrally and transported by car to vaccine centres.
64
Q
Vaccines: RNA-based COVID-19 vaccines
- Cell entry is achieved by packaging in …. These are … and may be … and destroyed by shaking.
- In the beginning, the mRNA vaccines were treated with extreme care. Doses were drawn up immediately prior to administration and a fair number of doses was discarded as a precaution e.g. after dropping syringes.
- In some countries the guidance for the Pfizer/Biontech vaccine, for example, has been adjusted a little bit, to the extent that vaccine doses can be drawn up centrally and transported by car to vaccine centres.
A
- Cell entry is achieved by packaging in liposomes. These are fragile and may be damaged and destroyed by shaking.
- In the beginning, the mRNA vaccines were treated with extreme care. Doses were drawn up immediately prior to administration and a fair number of doses was discarded as a precaution e.g. after dropping syringes.
- In some countries the guidance for the Pfizer/Biontech vaccine, for example, has been adjusted a little bit, to the extent that vaccine doses can be drawn up centrally and transported by car to vaccine centres.
